PROJECT SUMMARY Assay Development & HTS Core The Assay Development & HTS (ADHTS) Core will work in tandem with the other Technical Cores to achieve the overall ADDD CENTER mission of developing novel lead compounds for prioritized AD targets (Overall MILESTONE 3). To accomplish this, the ADHTS Core will perform primary and secondary assay enablement studies on selected targets to support compound screening and iterative structure activity relationship (SAR) studies. For targets that are advanced for lead discovery, the ADHTS Core will contribute to the design of a specific lead generation strategy and enable the in vitro testing flow scheme. This will include assays to support the specific molecular discovery approach (i.e. HTS, structure based design, fragment screening, etc.,), validation of identified hits in secondary assays, and iterative hit-to-lead SAR studies. The in vitro assays will include primary and secondary pharmacology characterization, as well as ADME/Tox surrogates and pharmaceutical properties measures. The in vitro assays will be complimented, in some cases, by related in silico models that will aid in molecular hypothesis testing and prioritization of molecules for physical experimentation. The ADHTS Core will be led by Dr. Zhong-Yin Zhang, an expert in HTS, the Director of the Institute for Drug Discovery and the faculty director of the high-throughput/high-content chemical genomics screening facility at Purdue University. The ADHTS core will be comprised of two dedicated staff-level scientists and two post- doctoral students. Additionally, staff within the Institute for Drug Discovery and the high-throughput/high-content chemical genomics screening facility will assist in Core activities. Importantly, Dr. Zhang and staff will be guided by an advisory board of experts with experience in industrial and academic assay development and HTS. The Specific Aims of the ADHTS Core are: Specific Aim 1: Identification of in vitro assay-amenable nominated targets. Specific Aim 2: Assay development and hit discovery via HTS for selected targets. Specific Aim 3: Hit-to-Lead studies.